In mammals, the receptors that respond selectively to noxious stimuli are known as nociceptors. Two distinct sets of peripheral sensory neurons are primarily responsible for the sensation of pain. The first, Aδ-nociceptive neurons, contain myelinated axons and are aroused primarily by noxious heat and mechanical stimuli. The second set of nociceptive neurons, which possess unmyelinated axons and are known as C fibers, are activated by high intensity, mechanical, chemical and thermal stimulation. Each of these sets of neurons has their cell bodies in the dorsal root ganglia. Their processes are pseudounipolar, with one axon that terminates in the periphery and one that terminates on neurons in the dorsal horn of the spinal cord.
Analgesia is the loss of sensitivity to pain without loss of consciousness. In recent years, the convergence of various lines of research demonstrates that analgesia can be produced by exogenous opioids, such as morphine, or endogenous opioids. This research has resulted in a model that explains the mechanism whereby pain is inhibited. See, for example, Kelly, D., “Central Representations Of Pain and Analgesia”, Principals of Neural Science, Kandel and Schwartz, Eds. (1985).
The first means known to man for inducing analgesia was through the use of plant-derived opioid narcotics such as morphine. Postsynaptic opioid receptors have been characterized and include the following three basic subtypes: mu (μ), delta (δ) and kappa (κ). Endogenous opioids that bind these opioid receptors and thereby produce analgesia include the met- and leu-enkephalins, as well as β-endorphin. Most of the clinically used opiates, such as morphine, activate the μ-opioid receptor subtype.
Stimulation of C-fiber primary afferent neurons associated with pain results in the release of the potent neuropeptides substance P, calcitonin gene related peptide (CGRP) and somatostatin, as well as the “fast” neurotransmitter glutamate. The activated enkephalinergic inhibitory neurons in turn exert presynaptic inhibitory control over the release of these neurotransmitters, thus blocking the sensation of pain.
Opioid compounds (opiates) such as morphine, while effective in producing analgesia for many types of pain, are not always effective since the development of tolerance occurs in most patients. The development of tolerance to the effects of opioids is one of the major problems in chronic pain management today. Regardless of the route of opioid delivery, patients complain of decreasing pain relief with time. Although recent studies suggest that constant delivery of opioids (e.g., infusion or transdermal patch) produces less tolerance than intermittent dosing (e.g., short-acting opioids, such as Vicodin) (Jhamandas, K H et al., “Spinal amino acid release and precipitated withdrawal in rats chronically infused with spinal morphine,” J Neurosci 16:2758-2766 (1996); Ibuki T et al., “Effect of transient naloxone antagonism on tolerance development in rats receiving continuous spinal morphine infusion,” Pain 70:125-132 (1997)), tolerance is still a significant issue. Recent studies with patients receiving chronic intrathecal opioids demonstrate that in some patients an increase in dose of up to 2-3 fold over a period of months is necessary to maintain adequate analgesic levels (Winkelmuller M et al., “Long-term effects of continuous intrathecal opioid treatment in chronic pain of nonmalignant etiology,” J Neurosurg 85:458-467 (1996); Paice J A et al., “Clinical realities and economic considerations: efficacy of intrathecal pain therapy,” J Pain Symp Manage 14:S14-26 (1997); Sallerin-Caute B et al., “Does intrathecal morphine in the treatment of cancer pain induce the development of tolerance?,” Neurosurgery 42:44-49 (1998)). A recent study of the intra-operative use of remifentanil indicates that rapid (within hours) tolerance to this μ-opioid agonist can occur (Guignard B. et al., “Acute opioid tolerance: intraoperative remifentanil increases postoperative pain and morphine requirement,” Anesthesiology 93:409-417 (2000)). Basic research on human cell lines indicates that a 30% reduction in, μ-opioid receptor molecular signaling pathways occurs as early as 24 hours in culture with a μ-opioid agonist (Elliot J. et al., “Tolerance to 1μ-opioid agonists in human neuroblastoma SH-SY5Y cells as determined by changes in guanosine-5′-0-(3-[35S]-thio) triphosphate binding,” Br. J. Pharmacol. 121:1422-1428 (1997)). However, most researchers would agree that tolerance develops more rapidly in rats than in humans. For example, many patients have been successfully treated with stable-dose morphine for more than six days (which is the time-course for the development of morphine tolerance in rats) without becoming completely tolerant to the analgesic effects of morphine.
While escalating opioid use is not only a medicolegal issue for many physicians, escalating intrathecal opioids can result in side effects, such as myoclonus (Glavina M J et al., “Myoclonic spasms following intrathecal morphine,” Anaesthesia 43:389-390 (1988); De Conno F et al., “Hyperalgesia and myoclonus with intrathecal infusion of high-dose morphine,” Pain 47:337-339 (1991)). This side effect does not usually occur if the dose of intrathecal opioids is limited to a morphine equivalent of 60-70 mg/day. Although most patients start at intrathecal doses of less than 5 mg/day, even a 2-fold increase per year results in toxic doses within four years. At high doses, these compounds additionally produce side effects, such as respiratory depression, which can be life-threatening. Opioid drugs also frequently produce physical dependence in patients. Dependence appears to be related to the dose of opioid taken and the period of time over which the subject takes it. For this reason, alternate therapies for the management of chronic pain are widely sought. In addition, compounds which serve as either a replacement for, or as an adjunct to, opioid treatment in order to decrease the dosage of analgesic compound required, have utility in the treatment of pain, particularly pain of the chronic, intractable type.
Non-opioid drugs, such as the non-steroidal anti-inflammatory drugs (NSAIDs) provide an alternative therapy for the treatment of pain. The mode of action of NSAIDs is believed to be through inhibition of cyclooxygenase, the enzyme responsible for biosynthesis of the prostaglandins. As analgesics, the NSAIDs lack many of the side effects on the CNS that are associated with the opioids and they do not result in the development of dependence. They are only effective, however, on low to moderate intensity pain, and are not generally useful for intense pain. In addition, they have undesirable side effects, including the propensity to induce gastric or intestinal ulceration as well as disturbances of platelet function.
Despite the wide range of analgesic substances available, still lacking are drugs and drug administration regimes that are effective in reducing severe pain without requiring dose escalation due to the development of tolerance.